Project Summary/Abstract
This is the resubmission of a grant entitled “Th1/Th17 Immune Regulation in Severe Allergic Asthma” (1 RO3
AI163794-01) which focuses on the mechanism of dendritic cell (DCs)-mediated regulation of Th1/Th17 immune
response in neutrophilic airway inflammation. The overall goal of the resubmission application is to gain new
knowledge about how metabolic reprograming of DCs contribute to immune priming and immune-polarizing
effector function(s) and how it predisposes and generate the inflammatory milieu in severe asthmatic airways.
We know from clinical and experimental evidence that respiratory infections, which are a common trigger for
asthma exacerbations and contribute to severe form of the disease, manifested a mixed granulocytic airway
inflammation comprising both neutrophils and eosinophils. Moreover, we believe that asthma exacerbations in
presence of infections leads to stimulate innate sensor STING (stimulator of interferon genes) pathways, as well
as skewing Th1/Th17 immune response in the airways. We recently reported that not only activation and
immune-priming function of DCs are coupled to profound alterations of the cellular metabolic state, but also it
comprises a DC-specific response modulated by the endogenous key metabolites (Jaiswal et al., Immun.
Inflamm. Dis, 2019). New and exciting preliminary data reveal that DC-specific increase of immune responsive
gene1 (Irg1), which decarboxylate cis-aconitate to produce immunoregulatory metabolite itaconate, in Th1/Th17
asthmatic lung relative to naïve controls presumably to help resolve airway inflammation. This induction of Irg1
is coupled with itaconate productions in DCs with house dust mite (HDM) and STING stimulations. Results show
that exogenous itaconate treatment restored mitochondrial respiration and the capacity of DCs to polarize CD4+
T cells, suggesting an immunoregulatory role of itaconate on DCs immune-priming function(s). The anti-
inflammatory effect of itaconate was translated in vivo, where adoptive transfer of itaconate treated DCs reduced
airway inflammation and T cell-mediated immune response relative to vehicle-treated DCs. From these pieces
of evidence we hypothesize that itaconate plays a distinct regulatory role in lung DCs and can be induced to limit
neutrophilic airway inflammation. To test this hypothesis, in Aim1, we will first determine if endogenous itaconate
is required for developing airway inflammation and Th1/Th17 immune response using Irg1 knockout mice. In
Aim2, we will determine whether exogenous treatment of the itaconate derivative exerts potential anti-
inflammatory properties in vivo. Taken together, these studies will expand on the limited knowledge of how
Irg1/itaconate axis regulates DC effector function and whether therapeutic interventions targeting the airways
could reduce or abolish Th1/Th17 immune response in severe asthma.